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Treatment of relapse of hematological malignancies following allogeneic hematopoietic SCT (allo-HSCT) remains very challenging and relies usually on the readministration of chemotherapy combined with donor lymphocyte infusion (DLI). To enhance DLI effectiveness, lymphodepletion (LD) with fludarabine (Flu) and/or CY before the injection of lymphocytes is an attractive modality to modify the immune environment, leading possibly to suppression of regulatory T cells (T reg ) and exposing the patient to cytokine activation. However, LD before DLI may lead to induction of deleterious GVHD. To avoid inducing overwhelming toxicity, we proceeded by escalating doses of both LD and DLI. Eighteen patients with various non-CML hematological malignancies who relapsed following allo-HSCT were treated with chemotherapy and LD-DLI or LD-DLI upfront. T-cell subpopulation and DC levels as well as cytokine plasma levels (IL-7, IL-15) were measured before and following LD-DLI. Cumulative incidence of acute grade II–IV GVHD was 29.4% similar to that reported in patients receiving DLI without LD. In addition, Flu alone with low dose of DLI was not associated with severe GHVD. CY/Flu at the respective doses of 600 mg/m 2 on day 1 and Flu 25 mg/m 2 /day on days 1–3 did not result in a marked decrease of T reg cells, nor in endogenous IL-7 and IL-15 production. However, a peripheral expansion of DCs was observed. These findings suggest that the escalated dose procedure appears safe and prevent overwhelming toxicity. A dose-limiting toxicity has not yet been reached.

Recovery of immunity is delayed in recipients of T-depleted grafts. Adoptive transfer of memory T-cells may improve immune response to common pathogens. A cohort of 53 patients with malignant ( n  = 36) and non-malignant conditions ( n  = 17) received TCR alpha/beta depleted grafts from haploidentical ( n  = 25) or MUD ( n  = 28) donors. Donor lymphocytes were depleted of CD45RA-positive cells. At a median of 48 days after transplantation, patients received DLI at 25 × 10 3 /kg CD3 cells from haploidentical or 100 × 10 3 /kg CD3 from MUD donors. Up to 3 doses of donor lymphocytes were administered at monthly intervals, escalating to 100 × 10 3 /kg in haploidentical transplants and 300 × 10 3 /kg in MUD transplants. At a median follow-up of 23 months, the cumulative incidence of de novo acute GVHD after DLI is 2% (1 of 43), while the rate of reactivation of preexisting aGVHD was 50% (5 of 10). The transplant-related mortality is 6%. The overall survival rates are 80% and 88% in malignant and non-malignant conditions, respectively. Among patients with absent CMV-specific immune reactivity at baseline ( n  = 31) expansion of CMV-specific T-cells was demonstrated in 20 (64.5%) within 100 days. Infusions of low dose donor memory T-lymphocytes are safe and constitute a simple measure to prevent infections in the setting of alpha/beta T cell-depleted transplantation.

Donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (alloSCT) can boost Graft-versus-Leukaemia (GvL) reactivity but may induce Graft-versus-Host-Disease (GvHD). It is essential to understand which factors besides timing, donor type, and dose influence DLI alloreactivity. We previously identified viral infections, ≥ 5% patient cells in bone marrow chimerism, and lymphopenia at the time of DLI as relevant factors for GvHD after DLI following alemtuzumab-based T-cell depletion. Here, we investigated these factors and the alloreactivity after DLI following alloSCT with posttransplant cyclophosphamide in 83 patients with acute leukaemia/myelodysplastic syndrome receiving a prophylactic or preemptive DLI. 5% had viral infections close to DLI, 6% had ≥ 5% mixed chimerism, and 17% had lymphopenia. 2-year cumulative incidence of GvHD requiring systemic treatment was low: 7% (95%-confidence interval 1–14%). 22 of the 28 patients with ≥ 1% mixed chimerism at the time of DLI (79%) converted to full-donor chimerism. None of these responders relapsed, indicating achievement of GvL despite the low incidence of GvHD. Our data show that DLI alloreactivity is determined by the conditions at the time of DLI which are influenced by the transplantation strategy. Adjusting the DLI dose based on these conditions may improve the balance between GvHD and GvL.

Donor lymphocyte infusion (DLI) is a therapeutic approach for relapse after hematopoietic stem cell transplantation (HSCT). Despite their reported efficacy, the evolution of DLI practices over time remains underexplored. This study provided a comprehensive analysis of DLI strategies and outcomes over 30 years at a single institution. A retrospective analysis was conducted on 75 patients who underwent DLI for disease relapse between April 1994 and March 2024. The primary endpoint was the 3-year overall survival (OS) rate after DLI. Secondary endpoints included the 100-day complete remission (CR) rate and incidence of acute graft-versus-host disease (GVHD). The median age at the first DLI was 49 years (range, 20-69 years). The most common underlying diseases in all 75 cases were acute myeloid leukemia (AML, n = 46) and myelodysplastic syndromes (MDS, n = 12). Until 2014, DLI was only performed in patients with AML (n = 14), MDS (n = 2), or chronic myeloid leukemia (n = 5). However, since 2015, patients with various diseases, including lymphoid malignancies, have also undergone DLI. Azacitidine was the most frequently used combination therapy with DLI (n = 34). Regimens including venetoclax and FLT3 inhibitors have been commonly used since 2019 (n = 18). The 3-year OS rate was 29.1% (95% CI, 18.8-40.2%). Factors negatively influencing OS included age ≥50 years and a high or very high refined disease risk index. The 100-day CR rate was 52.1%, and acute GVHD occurred in 25.3% of the patients, with no strong correlation between GVHD incidence and CR achievement. Among 18 patients who underwent three or more DLIs since 2018, 88.9% achieved remission following DLI or second HSCT, with a median follow-up of 949.5 days for survivors. This study highlighted the evolving trends in DLI practices and the diversification of combination therapies. Future research should focus on further validating these findings and optimizing DLI protocols to improve patient outcomes.

Radiation (RT), temozolomide (TMZ), and dexamethasone in newly diagnosed high grade gliomas (HGG) produces severe treatment-related lymphopenia (TRL) that is associated with early cancer-related deaths. This TRL may result from inadvertent radiation to circulating lymphocytes. This study reinfused lymphocytes, harvested before chemo-radiation, and assessed safety, feasibility, and trends in lymphocyte counts. Patients with newly diagnosed HGG and total lymphocyte counts (TLC) ≥ 1000 cells/mm 3 underwent apheresis. Cryopreserved autologous lymphocytes were reinfused once radiation was completed. Safety, feasibility, and trends in TLC, T cell subsets and cytokines were studied. Serial TLC were also compared with an unreinfused matched control group. Ten patients were harvested (median values: age 56 years, dexamethasone 3 mg/day, TLC/CD4 1980/772 cells/mm 3 ). After 6 weeks of RT/TMZ, TLC fell 69 % (p < 0.0001) with similar reductions in CD4, CD8 and NK cells but not Tregs. Eight patients received lymphocyte reinfusions (median = 7.0 × 10 7  lymphocytes/kg) without adverse events. A post-reinfusion TLC rise of ≥300 cells/mm 3 was noted in 3/8 patients at 4 weeks and 7/8 at 14 weeks which was similar to 23 matched controls. The reduced CD4/CD8 ratio was not restored by lymphocyte reinfusion. Severe lymphopenia was not accompanied by elevated serum interleukin-7 (IL-7) levels. This study confirms that severe TRL is common in HGG and is not associated with high plasma IL-7 levels. Although lymphocyte harvesting/reinfusion is feasible and safe, serial lymphocyte counts are similar to unreinfused matched controls. Studies administering higher lymphocyte doses and/or IL-7 should be considered to restore severe treatment-related lymphopenia in HGG.

Relapsed/refractory acute myeloid leukemia (R/R AML) carries an extremely poor prognosis, particularly in patients who fail chimeric antigen receptor T-cell (CAR-T) therapy, with no effective treatment options currently available. We report a 35-year-old male with AML who experienced relapse after multiple lines of high-intensity chemotherapy. Salvage CAR-CLL1 therapy was administered, but the patient failed to achieve hematopoietic recovery or immune reconstitution, followed by rapid disease relapse within one month and progression to septic shock. At this critical juncture, conventional therapies proved insufficient. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) includes peripheral blood stem cell transplantation (PBSCT) and umbilical cord blood (UCB). The patient underwent combined UCB and PBSCT with donor lymphocyte infusion (DLI). He has since achieved sustained remission, though developed cutaneous and intestinal graft-versus-host disease (GVHD), which is currently under control. This case highlights that combined UCB and PBSCT with DLI may represent a potential therapeutic option for R/R AML following CAR-T therapy failure, warranting further investigation in similar high-risk scenarios.

Donor lymphocyte infusions (DLI) are a standard therapy following allogeneic hematopoietic cell transplantation (alloHCT) for preventing and treating leukemic relapse in high-risk patients, particularly those with myeloid malignancies such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS). However, the efficacy of DLI remains suboptimal and is accompanied by a significant risk of life-threatening graft-versus-host disease (GvHD), highlighting the urgent need for strategies that enhance graft-versus-leukemia (GvL) effects while mitigating GvHD. We propose that engaging donors in an acute bout of exercise during peripheral blood lymphocyte collection represents a promising strategy to enhance GvL activity whilst mitigating the risk of GvHD. A single bout of cardiorespiratory exercise triggers catecholamine- and β 2 -adrenergic receptor-dependent mobilization of effector lymphocytes into the bloodstream, significantly increasing the proportion of GvL-promoting NK-cells and γδ T-cells relative to total CD3+ T-cells while reducing GvHD-promoting naïve CD4+ and CD8+ T-cells. Preclinical evidence suggests that these exercise-mobilized lymphocytes infiltrate tumors, exhibit enhanced leukemic control in xenogeneic mice, and display transcriptomic and proteomic profiles indicative of heightened anti-tumor immunity, migration potential and cytokine responsiveness. In this narrative review, we evaluate the advantages and limitations of DLI as a post-alloHCT therapy and propose the novel concept of exercise-enhanced donor lymphocyte infusions (DLI-X) as a simple and cost-effective strategy to augment GvL effects in preventing and treating leukemic relapse. Additionally, we propose that enriching DLI-X with NK-cell-enhancing cytokines (e.g., IL-12, IL-15, and IL-18) will create a novel therapeutic product, termed DLI-XS, with enhanced potency for post-alloHCT applications. We also discuss how DLI-X and DLI-XS, can be leveraged in combination with other post-transplant interventions to maximize GvL effects while minimizing GvHD risks. Finally, we explore the critical role of donor fitness (e.g. V̇O 2 max) in potentially influencing clinical outcomes of alloHCT and post-transplant cell therapies. This comprehensive integration of DLI-X and DLI-XS into existing treatment paradigms represents a promising avenue for enhancing therapeutic outcomes in leukemic relapse post-alloHCT and will underscore the transformative potential of exercise as an accessible and cost-effective adjuvant for DLI.

Objective Primary poor graft function (PGF) is a common and serious complication after haploidentical hematopoietic stem cell transplantation (haplo‐HSCT). This study retrospectively evaluates the efficacy and safety of a novel combination therapy consisting of low‐dose decitabine, donor lymphocyte infusion (DLI), and eltrombopag for the treatment of primary PGF subsequent to haplo‐HSCT. Methods In this analysis of ten patients, decitabine was administered at a dose of 7 mg/m2/day for three consecutive days, followed by DLI on the fifth day and eltrombopag, which was started at 50 mg/day and titrated up to 150 mg. The primary endpoints of the study encompassed hematologic recovery. Results Nine patients (90%) achieved a complete response with normalized blood counts, while one patient (10%) showed a partial response with transfusion independence. Adverse events included manageable graft‐versus‐host disease (GVHD) in four patients. Conclusion These findings indicate that this triple therapy represents a promising approach for the management of primary PGF following haplo‐HSCT.

Despite remarkable progress in survival with the availability of novel agents, an overwhelming majority of patients with multiple myeloma (MM) relapse and the curability of MM remains limited. Genetically defined high-risk MM represents a subgroup with an aggressive disease course despite novel agents. Allogeneic hematopoietic cell transplantation (allo-SCT) is a potentially curative option in MM that has several advantages including a tumor-free graft, and the potential for sustained immune-mediated disease control. However, historically high treatment-related mortality (TRM) and conflicting reports from prospective studies in the United States and European Union have limited the utilization of this modality. Meanwhile, newer preparative regimens, planned maintenance strategies and improvements in supportive care have led to a decline in TRM and better survival in recent years. The allo-SCT platform also provides additional options of immunotherapy at relapse including donor lymphocyte infusions, immunomodulatory drug maintenance and withdrawal of immune suppression. In this article, we provide an in-depth review of literature for allo-SCT and other immunotherapy options, as well as the authors’ approach to using allo-SCT in MM.

Post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication of hematopoietic stem cell transplantation caused by Epstein–Barr virus (EBV) reactivation due to immunosuppression. Frontline treatment includes the reduction of immunosuppressive therapy and administration of rituximab. However, the incidence of EBV-related PTLD (EBV + PTLD) continues to increase, and patient prognosis remains poor. In this retrospective study, we designed an exploratory treatment strategy for PTLD using designated reduced-dose donor lymphocyte infusion (DLI) (CD3 + T cells: 5 × 10 4 /kg) for majority patients (11/14). We further analyzed the data of 27 patients with PTLD who underwent transplantation at our institutions. Our therapeutic strategy effectively treated PTLD. In this study, the DLI cohort demonstrated higher overall response and complete remission rates than rituximab monotherapy after two-week intervention. Additionally, the DLI group had a markedly higher 1-year overall survival (OS) than the rituximab group. Similarly, the reduced-dosage DLI group had a significantly higher 1-year OS than the conventional-dosage group. These results indicate that varied treatments (rituximab vs DLI) and DLI dosages (conventional vs reduced) had significant impact on OS. Finally, the reduced-dosage DLI group had a lower risk of non-relapse mortality and acute graft versus host disease than the conventional-dosage group. This study demonstrates that reduced-dosage DLI is a promising treatment for EBV + PTLD.